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  Novel type ii na/pi cotransporters and type ii na/pi cotransporter expression regulatory factorsUSPTO Application #: 20070072236Title: Novel type ii na/pi cotransporters and type ii na/pi cotransporter expression regulatory factors Abstract: The present invention provides novel type IIc Na/Pi cotransporters. These cotransporters are important Pi transporters that are highly expressed during the growth period from the weaning stage to the adult stage. Furthermore, the present invention provides FGF23 and mutants thereof as factors that regulate the expression of type II Na/Pi cotransporters. FGF23 suppresses Pi reabsorption through suppression of type II Na/Pi cotransporter expression in kidneys. Therefore, FGF23 can be used as a target substance for regulating Pi reabsorption in kidneys. The present invention provides important factors for the development of preventive and therapeutic agents for hyperphosphatemia or hypophosphatemia. (end of abstract) Agent: Fish & Richardson PC - Minneapolis, MN, US Inventors: Keni-Ichi Miyamoto, Hiroko Segawa USPTO Applicaton #: 20070072236 - Class: 435007100 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Antigen-antibody Binding, Specific Binding Protein Assay Or Specific Ligand-receptor Binding Assay The Patent Description & Claims data below is from USPTO Patent Application 20070072236. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 10/747,032, filed Dec. 23, 2003, which claims the benefit of U.S. Provisional Application Ser. No. 60/436,386 filed Dec. 23, 2002, which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION [0002] The present invention relates to type II Na/P.sub.i cotransporters, more specifically to novel type II Na/P.sub.i cotransporters expressed in the kidneys of weaning mammals, and expression regulatory factors thereof. BACKGROUND OF THE INVENTION [0003] Inorganic phosphate (P.sub.i) is of critical importance to bodily functions, particularly during periods of growth. Kidneys contribute to the maintenance of the positive P.sub.i balance required for growth by reabsorbing a high fraction of the filtered P.sub.i (Pediatr. Nephrol. 16: 763-771). The capacity for Na.sup.+-dependent phosphate cotransport across the luminal brush border membrane of renal proximal tubular cells is greater in juveniles than in adults (Pflugers Arch. Eur. J. Physiol. 394:217-221; and Am. J. Physiol. 257:F268-F274). [0004] Several mammalian renal Na.sup.+-dependent P.sub.i cotransporters have recently been isolated and characterized (Physiol. Rev. 80:1373-1409). In the kidney cortex, the cDNAs of these transporters can be divided into three types (types I to III)(Physiol. Rev. 80:1373-1409). Type II Na/P.sub.i cotransporters belong to a unique class of Na.sup.+-coupled cotransport proteins. They can be further subdivided into two subgroups: type IIa and type IIb (Physiol. Rev. 80:1373-1409). Type IIa cotransporters are expressed in the proximal tubule of the kidney, whereas type IIb are expressed in several tissues such as the lungs and small intestine. The functional characteristics of type IIa Na/P.sub.i cotransporters, and the proximal tubular localization and expression of their mRNAs, suggest that these proteins represent a highly likely channel for the proximal tubular Na.sup.+-dependent entry of P.sub.i (Physiol. Rev. 80: 1373-1409). [0005] Age dependence was observed at the level of type IIa Na/P.sub.i cotransporter protein expression (Kidney Int. 50: 855-863; and Kidney 35 Int. 49: 1023-1026). In addition, a specific type IIa-related Na/P.sub.i cotransporter protein was postulated to account for high P.sub.i transport rates in weaning animals (Am. J. Physiol 273: R928-R933). Evidence for this was obtained by antisense experiments and transport expression in Xenopus oocytes (Pediatr. Nephrol. 16:763-771; and Am. J. Physiol. 273:R928-R933). When mRNA isolated from the kidney cortex of rapidly growing rats was treated with type IIa transporter antisense oligonucleotides, or was depleted of type IIa-specific mRNA using a subtractive hybridization procedure, Na.sup.+-dependent P.sub.i uptake was still detected in injected oocytes (Nephrol. 16:763-771; and Am. J. Physiol. 273:R928-R933). The type IIa transporter-depleted mRNA contained an mRNA species that showed partial sequence homology to the type IIa transporter which encodes the message. This conclusion is compatible with the observation that young type IIa (Npt2) knock-out mice lacking the type IIa mRNA and protein still retain their capacity to reabsorb P.sub.i at a rate that cannot be explained by the presence of type I and III Na/P.sub.i transporter (Proc. Natl. Acad. Sci. U.S.A. 95:5372-5377). Accordingly, this strongly suggests the possible existence of transporters as yet unidentified. [0006] Furthermore, the reabsorption of phosphate in kidneys has been studied using transporters that participate in the above-mentioned Pi-uptake, as well as regulatory factors in Pi-reabsorption. For example, the phosphorus (Pi) content of one's diet is a major regulator of proximal tubular Pi reabsorption, and has been extensively studied using isolated brush-border membrane (BBM) and cell cultures (Murer H., Hernando N., Forster I., and Biber J., "Proximal tubular phosphate reabsorption: molecular mechanisms." Physiol. Rev. 80: 1373-1409,, 2000). These studies demonstrate that changes in proximal Pi reabsorption capacity, as provoked by changes in dietary Pi content, are reflected in altered rates of apical Na+-dependent Pi cotransporters, but not in changes of the apparent Km value for Pi. The regulatory factors for these adaptive systems (dietary Pi) include parathyroid hormone (PTH), vitamin D, growth hormone, thyroid hormone, and calcitonin, but have been suggested to further include agents as yet unidentified (Murer H. et al., 2000, supra). [0007] In autosomal dominant hypophosphatemic rickets (ADHR), a phosphate-wasting disorder, the gene mutated in patients suffering form this disease has been identified as fibroblast growth factor 23 (FGF23), which is a protein that shares sequence homology with fibroblast growth factor 2 (FGF2) (Kruse K., Woelfel D., and Storm T. M., "Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation.", Horm Res 55: 305-308, 2001; and The ADHR Consortium. Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF23. Nat. Genet. 26: 345-348, 2000). The FGF23 protein is a novel, secreted protein that consists of 251 amino acids, comprising a putative N-terminal signal peptide (residues 1-24) (Nat. Genet. 26: 345-348, 2000). The missense mutations at 176Arg and 179Arg are responsible for ADHR (Kruse K. et al., 2001, supra; and Nat. Genet. 26: 345-348, 2000, supra). These amino acid residues are in the consensus proteolytic cleavage sequences represented by "RXXR". It is possible that mutations at 176Arg and 179Arg prevent proteolytic cleavage, so a large amount of the mutant protein consequently may be secreted as an intact form into a blood circulation (Yamashita T., Konishi M., Miyake A., Inui K., and Itho N., "Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway.", J. Biol. Chem., In press, 2002). Patients with ADHR display many of the clinical and laboratory characteristics observed in patients with oncogenic hypophosphatemic osteomalacia (OHO) (White K. E., Jonsson K. B., Carn G., Hampson G., Spector T. D., Mannstadt M., Lorenz-Depiereux B., Miyauchi A., Yang I. M., Ljunggren O., Meitinger T., Strom T. M., Juppner H., and Econs M. J., "The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting." J. Clin. Endocrinol. Metab. 86: 497-500, 2001). [0008] White et al. and Shimada et al. demonstrated that FGF23 is a secreted polypeptide overexpressed by tumors that cause Pi wasting (Non-Patent Document 9, White K. E. et al., 2001, supra). Patients with OHO share biochemical and clinical similarities with ADHR patients including hypophosphatemia, decreased or inappropriately normal serum 1,25(OH)2D3 concentrations, osteomalacia, and reduced tubular maximum reabsorption of Pi (TMP)/glomerular filtration rate (GFR) (Kruse K. et al., 2001, supra). Recently, the present inventors reported that the administration of naked DNA (FGF23 R176Q) to mice and rats caused the suppression of renal Pi transport activity and phosphaturic effects (WO02052009). However, the mechanisms by which FGF23 suppresses renal Pi transport activity, for example, what sort of target FGF23 acts on to induce suppression of renal Pi transport, have not been demonstrated. SUMMARY OF THE INVENTION [0009] An objective of the present invention is to provide novel type II Na/Pi cotransporter proteins, and to provide factors that regulate the expression of type II Na/Pi cotransporter proteins including the novel transporters. [0010] Upon extensive analysis to accomplish the above-mentioned objective, the present inventors succeeded in isolating a novel type II Na/Pi cotransporter expressed in kidneys, which is different from type IIa Na/Pi cotransporters. Furthermore, the present inventors elucidated that FGF23 suppresses the expression of the type II Na/Pi cotransporter to suppress the reabsorption of Pi in kidneys. [0011] This cotransporter is an important Pi transporter that is highly expressed during the growth period from the weaning stage to the adult stage. Therefore, type IIc Na/Pi cotransporters and genes thereof will be useful in studying, diagnosing, and treating diseases related to defects in Pi reabsorption. Furthermore, type IIc Na/Pi cotransporters and genes thereof are useful in screening for therapeutic agents for diseases relating to defects in Pi reabsorption. [0012] In addition, FGF23, which is a factor that regulates the expression of type II Na/Pi cotransporters, is itself the substance that regulates, or more specifically, suppresses the reabsorption of Pi in kidneys. It can be used as a target substance for regulation of Pi reabsorption in kidneys. Therefore, the present invention provides important factors in the development of preventive and therapeutic agents for hyperphosphatemia or hypophosphatemia. [0013] According to such findings, the present invention provides novel type II Na/Pi cotransporters specifically described below, and expression regulatory factors of type II Na/Pi cotransporters including these novel transporters. [0014] One aspect of the present invention relates to novel type II Na/Pi cotransporters, and this is specifically described below. [0015] [1] A protein selected from any one of the following (a) to (c) [0016] (a) a protein comprising the amino acid sequence of SEQ ID NO: 2; [0017] (b) a protein comprising the amino acid sequence of SEQ ID NO: 4; [0018] (c) a protein comprising the amino acid sequence of SEQ ID NO: 2 or 4, wherein one or more amino acids have been deleted, substituted, or added, wherein the protein comprises Na/Pi cotransporter activity. [0019] [2] A DNA encoding the protein of [1]. [0020] [3] The DNA of [2] selected from any one of the following (a) to (c): Continue reading... 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